DESCRIPTION (applicant's abstract): The overall long-term goal of our laboratory is to identify the neural circuitry and neurotransmitter receptors that mediate aggressive behavior. The objective of this grant application is to focus upon the role of substance P-neurokinin (NK1) receptors in the anterior medial hypothalamus. The rationale for this approach is based upon our recent preliminary findings that: (1) NK1 mRNA as well as NK1 receptors (as determined by receptor autoradiography) are present in the anterior medial hypothalamus of cat; (2) the powerful modulating effects of the amygdala and septal area upon defensive rage and predatory attack are mediated by NK1 receptors in the anterior medial hypothalamus; and (3) administration of SP agonists into the anterior medial hypothalamus suppresses predatory attack behavior. On the basis of these findings, we propose that NK1 receptors are critical to understanding the neural mechanisms of aggression. Our hypothesis is that NK1 receptors in the anterior medial hypothalamus mediate the potentiation of defensive rage and the suppression of predatory attack. Five experiments are proposed to test this hypothesis. The first will utilize in situ hybridization to identify and characterize the distribution of mRNA for NK1 in the medial hypothalamus. The second will test our hypothesis that activation of NK1 receptors in the anterior medial hypothalamus will potentiate defensive rage and suppress predatory attack. The third will determine whether other neurokinin receptors (i.e., NK2 and NK3 receptors) in the medial hypothalamus also regulate these forms of aggression. The fourth experiment will test the concept that the anterior medial hypothalamus and midbrain periaqueductal gray (PAG) comprise key structures of a single neural substrate for defensive rage by observing the effects of NK1 receptor activation of the anterior medial hypothalamus upon defensive rage elicited from the PAG. The fifth will systematically test whether NK1 receptors in the anterior medial hypothalamus mediate septal area modulation of defensive rage elicited from the medial hypothalamus or PAG, and predatory attack elicited from the lateral hypothalamus. It is our view that the proposed experiments will provide new insights into the organization of the brain mechanisms that regulate rage and aggression by characterizing the functional properties of NK1 receptors in the anterior medial hypothalamus. Such insights may provide a rational basis for the development of serenic drugs for the treatment of aggressive disorders.